Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a protein kinase A activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g. synthesis or processing mutations) or impair channel function (e.g. gating or conductance mutations) or both.
PCT publication No. WO 2011/113894 describes compounds which restore or enhance the function of mutant and/or wild type CFTR for the treatment of cystic fibrosis, primary ciliary dyskinesia, chronic bronchitis, chronic obstructive pulmonary disease, asthma and other CFTR related diseases. The compounds described therein include (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide (Example 5 of WO 2011/113894).
The synthesis described in WO 2011/113894 to make (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide is long, uses expensive starting materials and toxic reagents. Schemes 1 and 2 outline a synthesis from WO 2011/113894 used to make(S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide.

In Scheme 1, the intermediate ethyl 3-amino-5-(trifluoromethyl)picolinate (B4) is made via a Buchwald-Hartwig coupling reaction which requires the use of an expensive starting material (B1) and an expensive palladium catalyst which has to be controlled in the final product. Also, the conversion of B4 to B5 requires the use of NBS, a mutagenic reagent which has to be controlled in the API.

Moreover, the conversion of B5 to B8 is accomplished through the addition of 2,5-hexanedione, a well-known neurotoxin, as shown in Scheme 2. Transformation of the pyrrole in B8 to the amine B9 uses hydroxylamine which is a mutagenic and thermally unstable compound that is dangerous to use in large quantities. The overall process described in WO 2011/113894 requires many protecting group manipulations that lead to a low atom economy and afford a lot of waste. Thus there is a need for an improved synthetic process for making (S)-3-amino-6-methoxy-N-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-5-(trifluoromethyl)picolinamide.